The aim of this proposal is to study the role of natural suppressor (NS) cells in cancer therapy and in tolerance induction. NS cell activity is nonspecific, MHC unrestricted, and does not act through a cytolytic mechanism. NS cell activity is found in several normal locations such as bone marrow and newborn spleen. It is induced and found in large quantities after such treatments as total lymphoid irradiation, cyclophosphamide (CY), and during graft-vs-host disease in a murine model of bone marrow transplantation. The hypothesis that I am working on is that NS cells are natural immunoregulators which are important to the outcome of cytoreductive therapies commonly used in cancer therapy and as immunosuppressive treatments in transplantation. I intend to mainly study murine NS cell activity which is induced after CY injection and which is found normally in newborn spleen. The specific aims of this proposal are to: 1. Investigate whether NS cells can regulate the development and activity of natural killer (NK) cells. 2. Investigate whether NS cells can regulate the generation and activity of lymphokine activated killer (LAK) cells. 3. Study the regulation of NS cell development and activity. 4. Utilize lymphokine activated suppressor (LAS) cells to study the immunosuppressive and tolergenic potential of NS cells both in vitro and in vivo. 5. Develop NS cell clones and antibodies to NS cells. 6. Further investigate the genetics of NS cell activity through the development of an in vitro assay for